P586: IADADEMSTAT COMBINATION WITH AZACITIDINE SHOWS ENCOURAGING SAFETY AND EFFICACY DATA IN ELDERLY AND UNFIT AML PATIENTS
Authors: O. Salamero, T. Somervaille, A. Molero, E. Acuña-Cruz, J. A. Perez-Simon, R. Coll, M. Arnan Sangerman, B. Merchan, A. Perez, I. Cano, R. Rodriguez-Veiga, M. Arevalo, S. Gutierrez, C. Buesa, F. Bosch, P. Montesinos
Journal: HemaSphere (2022)

Background: Acute Myeloid Leukemia (AML) is an hematological malignancy with highest incidence and lower survival rates in elderly. Previously reported ORR with hypomethylating agents such as azacitidine alone is less than 30%. Recently, combinations of hypomethylating agents with venetoclax have shown improved response ratios. However, refractoriness or relapse is still a challenge for most patients (pts), particularly in the elderly and the high-risk subpopulations. It has been shown that LSD1 is involved in malignant transformation in AML. Iadademstat (iada) is a potent and selective LSD1 inhibitor that has been administered to more than 100 oncology pts in Ph1 and Ph2 trials, showing manageable toxicity and signs of preliminary activity. Aims: ALICE (EudraCT 2018-000482-36) is a Phase IIa study to assess the safety, tolerability and the recommended Phase II dose (RP2D) of iada (PO 5d ON, 2d OFF every week in 28d cycles) in combination with azacitidine (sc., d1-5 and 8-9 every cycle) for the treatment of adult patients diagnosed with AML, as per WHO 2016 classification, who have not received prior treatment and are ineligible for intensive chemotherapy. We present an update of the ongoing study six months after completion of recruitment. Methods: Two doses of iada are studied in the trial: 60 and 90µg/m2/d. Besides the safety and tolerability primary endpoints, secondary endpoints investigate anti-leukemic activity including ORR according to ELN recommendations, time to response (TTR) and duration of responses (DoR). Additional assessments include residual detectable disease status, overall survival and PK/PD determinations. Results: At EHA 2021, ALICE data from 27 pts were reported. In October 2021, recruitment of the targeted 36 pts was completed. Patient baseline characteristics are shown in Table 1. Main safety events by the end of 2021 included 348 adverse reactions (AR). The most frequently reported AR was platelet reduction, observed in 44% of pts, however, Grade ≥3 thrombocytopenia was already present at baseline in 61% of pts (Table 1). Only three Grade 3-4 nonhematological treatment-related ARs were observed in two pts (asthenia, dysgeusia and weight decrease). Among the 71 serious AR reported, only 2 were considered as potentially related to iada, corresponding to a differentiation syndrome and a fatal intracranial hemorrhage, previously presented at EHA 2021. By the time this abstract is written, among the pts intended to treat (34), 27 have had at least 1 bone marrow evaluation after cycle 1 and are therefore evaluable for efficacy. 78% of them (21 of 27) achieved an objective response; of which, 62% were CR/CRi. Moreover, 80% of the CRi pts also achieved partial hematology recovery (CRh). Among CR/CRi pts, 5 out of the 8 already assessed by MRD presented no residual detectable disease by flow cytometry. DoR is encouraging with 77% of the CR/CRi lasting more than 6 months, with a mean DoR increasing as the study progresses, with the longest CR to date above 1,100 days. Iada at 90 µg/m2/d is the confirmed RP2D for the combination, showing deep responses with manageable toxicity. Image:Summary/Conclusion: ALICE data confirms that the combination of iada with azacitidine gives robust, fast and durable responses in unfit, previously untreated, AML patients. Considering iada’s efficacy, pharmacologic properties, its manageable toxicity and low anticipated drug-drug interactions, iada combinations may offer additional therapeutic options for AML patients in first line or in the R/R setting.